Tenofovir, is chemically, 9-[2-(R)-(phosphonomethoxy) propyl]adenine (PMPA). Tenofovir disoproxil is a pro-drug of Tenofovir. It has increased oral bioavailability compared to Tenofovir. Tenofovir is approved for commercial use as in the form of Tenofovir disoproxil fumarate (TDF), chemically known as 9-[(R)-2-[[bis[[(isopropoxycarbonyl)oxy]-methoxy]phosphinyl]methoxy]propyl]adenine fumarate (1:1).
Tenofovir Disoproxil Fumarate 300 mg Tablets are indicated in combination with other anti-retrovirals for the treatment of HIV-1 infection in adults and adolescents aged over 12 years. Tenofovir Disoproxil Fumarate 300 mg Tablets are indicated for the treatment of chronic hepatitis B in adults and adolescents aged over 12 years with compensated liver disease, with evidence of active viral replication, persistently elevated serum alanine aminotransferase (ALT) levels and histological evidence of active inflammation and/or fibrosis.
Tenofovir disoproxil fumarate (TDF) is observed to have poor flow properties, therefore aqueous or non-aqueous wet granulation is a preferred processing step in the formulation of the TDF tablets, by most pharmaceutical manufacturers. Also, as per International Journal of Drug Development & Research, 2012, Volume 4, Issue 1, Pages 247-256; for Emtricitabine and Tenofovir disoproxil fumarate film coated tablets, wet granulation with pregelatinized starch as binder was found to be the best method of choice for formulation of these tablets, as compared to direct compression.
Literature is also available on non-wet granulation techniques for compounding Tenofovir. For example—EP 2389929A1 discloses compositions of Tenofovir with pregelatinized starch (5-15%) by weight prepared by direct compression. IN 2621/CHE/2013 discloses a hot-melt extruded Tenofovir disoproxil composition having a binder. 843/CHE/2013 discloses an extrusion-spheronization process for preparation of oral multi-particulate compositions composed of Tenofovir coated with ethyl cellulose or methacrylic acid co-polymers. CN103330683 B discloses hot-melt extrusion of Tenofovir disoproxil fumarate with sweetener and polymer Kollidon® VA64, Kollicoat® IR and Soluplus® to prepare fine granules. European Patent Document EP1890681 B1 describes a method comprising dry granulating a composition comprising a pharmaceutically acceptable excipient, emtricitabine and tenofovir DF to produce dry granules.
However, none of the references suggest or disclose free flowing directly compressible Tenofovir granules devoid of an excipient, or a process for preparation of such granules. Such granules would be specifically more advantageous in case of unit dose antiretroviral oral fixed dose combinations where there is a larger percentage of API in the finished dosage form. For example—Atripla® tablets, Complera® tablets, Stribild® tablets, Emtricitabine 200 mg/Tenofovir disoproxil fumarate 300 mg+Nevirapine 200 mg tablets, etc. Besides, since TDF is sensitive towards hydrolytic degradation. It would be highly desirable to process TDF in conditions which can prevent or minimize such hydrolytic degradation. Further, it would be most desirable to prepare free flowing directly compressible Tenofovir granules devoid of an excipient which can remain stable at 40° C. and 75% relative humidity for three months.
As per, Authorized USP Pending Monograph Version 1; following are the impurities known for Tenofovir Disoproxil Fumarate—
Tenofovir isoproxil monoester—({[(R)-1-(6-Amino-9H-purin-9-yl) propan-2-yloxy]methyl}(hydroxy)phosphoryloxy)methyl isopropyl carbonate
Tenofovir isopropyl isoproxil—O-(Isopropoxycarbonyloxymethyl)-O-isopropyl-{(R)-[1-(6-amino-9H-purin-9-yl) propan-2-yloxy]}methylphosphonate
Tenofovir disoproxil ethyl ester—O-(Ethoxycarbonyloxymethyl)-O-(isopropoxycarbonyloxymethyl)-{(R)-[1-(6-amino-9H-purin-9-yl) propan-2-yloxy]}methylphosphonate
Tenofovir disoproxil carbamate—O,O-Bis(isopropoxycarbonyl oxymethyl){(R)-1-[(6-isopropoxycarbonylamino)-9H-purin-9yl]propan-2-yloxy]}methylphosphonate and
Tenofovir disoproxil dimer—Tetra(isopropoxycarbonyloxymethyl) (2S)-1,1′-[6,6′-methylenebis(azanediyl)bis(9H-purine-9,6-diyl)bis(propane-2,1-diyl)bis(oxy)bis(methylene)diphosphonate.
In view of increasing demand for Tenofovir products, sources of quality-assured Tenofovir are constantly needed for the production of good-quality finished dosage forms. Also, TDF API (Active Pharmaceutical Ingredient) or dosage forms, with tighter specifications for impurities would be highly desirable.